Skin manifestations following anti‐COVID‐19 vaccination: A multicentricstudy from Turkey

Abstract Purpose After the emergence of the pandemic caused by the COVID‐19 virus, vaccination with various vaccines has started to be implemented across the world. To identify dermatological reactions developing after the COVID‐19 vaccines administered in Turkey and determine their clinical features and risk factors that may play a role in their development. Materials and Methods The study included patients aged ≥18 years, who presented to 13 different dermatology clinics in Turkey between July 2021 and September 2021 after developing dermatological reactions following the administration of the COVID‐19 vaccine. After providing written consent, the patients were asked to complete a standard survey including questions related to age, gender, occupation, comorbidities, the regular medication used, the onset of cutaneous reactions after vaccination, and localization of reactions. Dermatological reactions were categorized according to whether they developed after the first or second dose of the vaccine or whether they occurred after the inactivated or messenger RNA (mRNA) vaccine. The relationship between dermatological reactions and some variables such as gender and comorbidities was also evaluated. Results A total of 269 patients [116 women (43.1%), 153 men (56.9%)] were included in the study. It was observed that the dermatological diseases and reactions that most frequently developed after vaccination were urticaria (25.7%), herpes zoster (24.9%), maculopapular eruption (12.3%), and pityriasis rosea (4.5%). The rate of dermatological reactions was 60.6% after the administration of the mRNA vaccine and 39.4% after that of the inactivated vaccine. There was a statistically significantly higher number of reactions among the patients that received the mRNA vaccine (p = 0.001). Conclusion The most common reactions in our sample were urticaria, herpes zoster, and maculopapular eruption. Physicians should know the dermatological side effects of COVID‐19 vaccines and their clinical features.


| INTRODUC TI ON
In December 2019, a large number of unexplained and fatal pneumonia cases emerged in Wuhan. The disease caused by the SARS-CoV-2 virus, which is the agent isolated from the lower respiratory tract of infected patients, was named as coronavirus disease. The virus quickly spread across the world, causing a large number of deaths. In March 2020, the World Health Organization declared the disease a pandemic. 1,2 The coronavirus disease has a high rate of mortality, especially in elderly people and those with comorbidities. In order to prevent the spread of the virus and minimize associated negative effects, vaccine studies were started promptly. The results of the phase 3 study of the German-origin Pfizer-BioNTech messenger RNA (mRNA) vaccine were finally presented to the U.S. Food and Drug Administration, which granted emergency use permission for this vaccine to be used in healthcare workers and high-risk patients in December 2020. 3 For the inactivated Sinovac vaccine, phase 1/2 studies were carried out in China, and phase 3 studies were initiated in Brazil, Indonesia, Turkey, and China after receiving approval from the Chinese National Medical Products Administration to conduct human clinical trials in April 2020. In October, the inactivated vaccine was approved for use in high-risk individuals. 4 In Turkey, the Sinovac vaccine started to be administered as of January 2021 and the mRNA BioNTech vaccine as of March 2021.
With the implementation of COVID-19 vaccines across the world, various dermatological diseases related to these vaccines, such as post-vaccine urticaria, herpes zoster, radiation recall phenomenon, and Steven Johnson syndrome, have been reported. [5][6][7][8] New reports on the side effects of vaccines continue to be published every day, and it is expected that there will be more reports on this fairly new vaccine application in the coming period.
In this study, our aim was to determine dermatological reactions due to the COVID-19 vaccines administered in Turkey, their onset and clinical features, and risk factors that may play a role in their development.

| MATERIAL AND ME THODS
This cross-sectional observational study included patients aged ≥18 years, who presented to 13 different dermatology clinics in Turkey between July 2021 and September 2021 after developing dermatological reactions following the administration of the COVID-19 vaccine. After providing informed consent, the patients were asked to complete a standard survey including questions related to age, gender, occupation, comorbidities, regular medications used, onset of cutaneous symptoms after vaccination, localization of reactions, type of vaccine administered applied, whether there was any symptom, whether they experienced a similar health problem before, and they had a history of COVID-19. The patients were followed up, and for each patient, it was noted how many days it took for cutaneous symptoms to regress. according to whether they developed after the first or second dose of the vaccine or whether they occurred after the inactivated or messenger RNA (mRNA) vaccine. The relationship between dermatological reactions and some variables such as gender and comorbidities was also evaluated.

Results:
A total of 269 patients [116 women (43.1%), 153 men (56.9%)] were included in the study. It was observed that the dermatological diseases and reactions that most frequently developed after vaccination were urticaria (25.7%), herpes zoster (24.9%), maculopapular eruption (12.3%), and pityriasis rosea (4.5%). The rate of dermatological reactions was 60.6% after the administration of the mRNA vaccine and 39.4% after that of the inactivated vaccine. There was a statistically significantly higher number of reactions among the patients that received the mRNA vaccine (p = 0.001). The demographic characteristics of the patients are summarized in Table 1.
The rate of dermatological reactions was determined as 60.6% after the mRNA vaccine and 39.4% after the inactivated vaccine.
There was a statistically significant higher number of reactions among the patients that received the mRNA vaccine (p = 0.001) ( Figure 2).
At the time of presentation, the rate of patients who had received the first dose of BioNTech was 46.5%, while the rate of those who had received the second dose of the BioNTech vaccine was 14.1%. For the Sinovac vaccine, these rates were 15.6 and 23.8, respectively ( Table 1).  Table 4. The number of symptomatic patients was 267 (99.26%), and the three most common symptoms were itching, pain, and burning sensation. Antihistamine and topical steroid treatments were sufficient in most cases. A considerable percentage of dermatological reactions (30.4%) regressed in three to 7 days (Table 4).
In the analyses performed to determine factors that played a role in the development of dermatological reactions following vaccination, the rate of these reactions was found to be statistically significantly higher in the men (56.9%) than in the women (43.1%) There was no significant difference between the <50 and ≥ 50 years groups in terms of the development rates of dermatological reactions (50.2% and 49.8%, respectively; p > 0.5).

TA B L E 4 Distribution of dermatological reactions by onset time or regression time and type of vaccine.
Onset time

| DISCUSS ION
It has been observed that urticaria, redness, edema, and injection site reactions may occur in phase 3 studies on the subcutaneous side effects of COVID-19 vaccine. 9,10 In the current study, the patients most developed urticaria In our study, herpes zoster was the second most common cutaneous reaction in the whole sample (24.9%). When the vaccine groups were groups, the rate of herpes zoster was significantly higher in the inactivated vaccine than in BioNTech (14.5% and 10.41%, respectively). In the literature, it has been reported that herpes virus reactivation occurs after influenza, hepatitis A, and rabies vaccines. 16 It has been considered that immunomodulation, which includes alloreactivity caused by inactivated hepatitis B vaccines and suppression of cellular immunity through live vaccines, can cause herpes virus reactivation. 17 Therefore, it is suggested that immunodysregulation after COVID-19 vaccination may result in herpes zoster reactivation. 18 In a study, the authors observed that herpes zoster developed in 10% of patients after the second dose of the Pfizer-BioNTech vaccine. 11 In another study conducted in Spain, herpes zoster and herpes simplex reactivation was reported at a rate of 13.8%. 19 In the same study, the most common cutaneous side effect of the Pfizer-BioNTech, was determined as herpes zoster reactivation at a rate of (17.2%). This finding was compatible with our study's result.
In our study, the rate of patients who developed pityriasis rosea  In the current study, cutaneous side effects were observed in 163 of the patients that had been administered the mRNA vaccine and 106 of those that had received the inactivated vaccine. The rate of dermatological side effects was statistically significantly higher in the mRNA vaccine group than in the inactivated vaccine group Ilteris Oguz Topal involved in literature review.

ACK N OWLED G M ENTS
We thank Dr. Mustafa Durmuscan for his support regarding of the statistical analysis.

CO N FLI C T O F I NTE R E S T
None.

E TH I C A L A PPROVA L
This study was approved by the Ethics Committee of the Prof.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly available in [repository name] at [DOI].

FI N A N CI A L S U PP O RT
None.